The goal of this program is to develop and ultimately commercialize small molecule drugs for the treatment of high risk pediatric B-cell acute lymphoblastic leukemia (B-ALL), with an initial focus on drug resistant B-ALL. B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy and is one of the leading causes of death in children. B-ALL primarily affects children between the ages of 2 and 7. Although over 90% of children with ALL experience complete remission, 20-25% of patients experience relapses resulting in poor prognosis. A leading cause of relapse in B-ALL is multidrug resistance (MDR) to a variety of cytotoxic drugs, including glucocorticoids, L-asparaginase, anthracyclines, and vinca alkaloids (vincristine). Despite decades of research and the identification of various MDR mechanisms, there is no real clinical solution to MDR. Further, increases in ALL survival over the past 50 years have been due largely to modifications in the use of existing therapies rather than the development of new drugs. New drugs with novel mechanisms of action that overcome MDR in relapsed, refractory disease are desperately needed. NovoMedix has recently identified two lead series that represent novel classes of drugs for the treatment of multi-drug resistant B-ALL with improved safety profiles compared to conventional therapies that could significantly improve outcomes for relapsed patients. Lead compounds have unique structures, nM IC50s in several B-ALL models, including multi-drug resistant B-ALL, are safe in vitro and in vivo, and have synergistic effects with commonly used chemotherapeutic agents, indicating that they may have different and/or complementary mechanisms of action and potential utility in relapsed patients. Phase I specific aims are: 1) SAR optimization and demonstration of safety in normal human cells and efficacy in a multi-drug resistant cell model and in relapsed, refractory, human B-ALL patient samples; 2) confirm mechanism of action; 3) determine in vivo PK and safety profile; and 4) demonstrate in vivo efficacy in animal models of multi-drug resistant B-ALL. Drug candidates that show potent inhibition of B-ALL tumor growth in the human-mouse xenograft model with little or no toxicity will be advanced to Phase II for additional safety and efficacy studies with the goal of filing an IND at the end of Phase II as an orphan drug candidate. PUBLIC HEALTH RELEVANCE: The ultimate goal of this program is to develop and ultimately commercialize small molecule drugs for the treatment of drug resistant B-cell acute lymphoblastic leukemia (B-ALL). B-ALL is the most common childhood malignancy and is one of leading causes of death in children, generally due to relapse as a result of multiple drug resistance.